The present invention concerns pharmaceutical compositions for the treatment of levodopa-induced dyskinesia and tardive dyskinesia.
Parkinson""s disease is an age related, progressive neurodegenerative disorder. The prevalence rate is approximately 0.5% in the population aged 50-59, 1% in ages 60-69, 2% in the 70-79 age group and rises to over 3% in those who are 80 and older. Prevalence rates are similar in Europe.
Parkinson""s disease is characterized by a relatively selective degeneration of dopaminergic neurons in the substantia nigra pars compacta with loss of striatal dopamine. The pathology shows depigmentation of the substantia nigra and intracellular inclusions (Lewy bodies). The cardinal features of the disease include resting tremor, rigidity, bradykinesia and postural instability. Current treatment of the motor signs of Parkinson""s disease is based on dopamine replacement. This involves the administration of levodopa, usually combined with a decarboxylase inhibitor. Exogenous levodopa is converted in the striatum to dopamine and replenishes the reduced dopaminergic concentrations in the basal ganglia. Dopamine agonists may be helpful as well. During the first years of treatment the patients enjoy a smooth and stable response to this treatment. However, after 2-5 years of chronic treatment with dopaminergic preparations, 75% of patients develop disabling and incapacitating motor complications. One of the most common side effects is the levodopa-induced dyskinesias (choreiform and dystonic involuntary movements). They occur in the majority (80-100%) of the patients as their illness progresses. Dyskinesias may be initially mild but they can become more and more progressive, complex, generalized, violent, and may severely interfere with motor function, speech, coordination and postural stability. Patients and families are often shameful by the unaesthetic and bizarre movements which can affect facial muscles, eyelids, mouth, cheeks, lips and tongue, upper and lower limbs and even trunk and respiratory muscles. This is one of the major reasons for social decline of afflicted patients.
At the beginning, when they first emerge, dyskinesias are mainly the peak-dose type, i.e., they are most prominent when levodopa plasma levels are high. When patients later develop response fluctuations after chronic levodopa treatment, dyskinesias may also appear at the beginning and again at the termination of an individual levodopa dose beneficial effect. When disease is more advanced, dyskinesias predominate in an xe2x80x9call or nonexe2x80x9d fashion, i.e., they are present throughout the duration of an xe2x80x9conxe2x80x9d period, induced by a successful single oral dose of levodopa. Such levodopa-induced dyskinesias also represent a major limiting factor in the pharmacological treatment of Parkinson""s disease.
When their illness progresses, the patients need increases in their daily levodopa dosage and the addition of other dopaminergic agents, e.g., dopamine agonists and MAO-B inhibitors. This is invariably associated with a rapid and intolerable increase of the frequency, distribution and severity of dyskinesias necessitating reduction of drugs. Dyskinesias are probably and primarily caused by the action of excessive exogenous dopamine on denervation-supersensitive post-synaptic dopaminergic receptors. Normally, the dopamine formed from levodopa is stored in vesicles within the dopaminergic nerve-endings for regulated release into the synapse. As the disease progresses, more nigral dopaminergic neurons degenerate and there is more severe loss of their nerve-terminals in the basal ganglia (caudate and putamen nuclei).
It is believed that the decarboxylation of exogenous levodopa therefore shifts to non-dopaminergic striatal compartments. Since the generated dopamine molecules are not stored, they immediately interact and hyperactivate the postsynaptic dopaminergic receptors (mainly of the D2 subtype) resulting in the involuntary movements. There is no satisfactory treatment for this type of dyskinesia. Discontinuation or reduction of levodopa and other dopaminergic drugs or addition of neuroleptic drugs that block dopaminergic receptors, can abolish the abnormal movements, but at the expense of severe aggravation of the parkinsonian symptoms. The control-release levodopa preparations have been proven unhelpful. This despairing state of affairs suggested that it would be difficult if not impossible to dissociate the beneficial anti-parkinsonian from the bad dyskinetic producing effects of levodopa.
Behavioral and psychiatric disorders are usually treated administration of by various anti-psychotics, also termed: xe2x80x9cneuroleptic drugsxe2x80x9d, the majority of which act by blockage of dopamine D2 receptor. Prolonged administration of anti-psychotic drugs often results in development of involuntary movements, termed: xe2x80x9ctardive dyskinesiaxe2x80x9d.
Riluzole (2-amino-6-trifluoromethoxy benzothiazole) has recently emerged as a pharmacological agent potentially useful to slow down the evolution of neurodegenerative diseases, such as amyotrophic later,a sclerosis. (Ben Simon et al., New Engl. J. Med., 330:585-91 (1994)). In addition, this molecule has been shown to display anticonvulsant, anti-ischemic, and neuroprotective properties under various experimental conditions. A clear understanding of the site and mechanism of action of this molecule is still lacking.
There has been recently a report (Palfi et al. Exper. Neurol 146 135-141 (1997)) that riluzole reduces various abnormal motor movement in baboons which were induced by 3-nitropropionic acid, serving as a model for progressive striatal degeneration, which is a model for Huntington""s disease.
The present invention provides, by one of its aspects, a pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardive dyskinesia, comprising as an active ingredient, a pharmaceutically effective amount of riluzole.
The present invention provides, by another of its aspects, use of riluzole for the preparation of a pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardive dyskinesia.
The term xe2x80x9cameliorationxe2x80x9d refers to a decrease in the abnormal involuntary movements characterizing these two types of dyskinesia, as can be determined for example, by using the Abnormal Involuntary Movement Scale (AIMS) as will be specified hereinbelow.
The term xe2x80x9clevodopa-induced dyskinesiaxe2x80x9d refers to dyskinesia, i.e. involuntary choreiform movements, brought about by the chronic administration of levodopa, for example in patients suffering from Parkinson""s disease.
The term xe2x80x9ctardive dyskinesiaxe2x80x9d refers to dyskinesia brought about by the chronic administration of neuroleptic, anti-psychotic drugs of the Dopaminergic-receptor blocker type.
The term xe2x80x9criluzolexe2x80x9d refers to 2-amino-6 trifluoromethoxy-benzothiazole.
The term xe2x80x9ceffective amountxe2x80x9d refers to an amount that brings about to a reduction in the AIMS of the patients without causing severe side effects.
The dosage of the active ingredient should be tested empirically for each specific indication, and depends on various factors, such as the patient""s weight, the length of time of administration of the levodopa or the neuroleptic pharmaceutical composition, age, etc. Generally speaking, the dosage should be of about 25 to about 200 mg per day, preferably of about 50 to about 200 mg per day, most preferably of about 50 to about 100 mg per day.
The pharmaceutical composition of the invention, may comprise olely riluzole and a pharmaceutically acceptable carrier.
Alternatively, it is possible to include in one dosage form, both the dyskinesia causing agent such as the neuroleptic drug (in the case of tardive dyskinesia), or levodopa (in the case of levodopa-induced dyskinesia) together with the riluzole.
The present invention further concerns a method for ameliorating levodopa-induced dyskinesia or tardive dyskinesia by administering to a subject in need of such treatment, a therapeutically effective amount of riluzole.
According to the-method of the present invention, the riluzole may be administrated separately, i.e. not simultaneously with the dyskinesia-causing agent (such as the neuroleptic drug or the levodopa), or alternatively may be administered together with the dyskinesia-causing agents either by administration of the two medicaments simultaneously or by forming both medicaments in a single dosage form.
The invention will now be described with reference to some non-limiting examples.